tbuckley/cabot-search huggingface dataset:
Abstract 4261: Genomic landscape of 2128 thyroid cancers from the aacr genie database: Implications for targeted therapies
Authors: Blessie Elizabeth Nelson, Mohammed Gouda, Jason Roszik, Mimi L. Hu, Maria Cabanillas, Vivek Subbiah
Journal: Cancer Research (2023)

Abstract Background: Understanding molecular biology of thyroid cancer has revolutionized diagnosis, tumor classifications and identifying effective precision oncology therapies. Methods: Using AACR GENIE database v.12, we cataloged genetic and co-occurring alterations in all thyroid cancers. Results: We identified 2128 cases from 153,834 samples where tumor sub-histologies included Papillary Thyroid Cancer (PTC: 55%; 1162), Poorly Differentiated Thyroid Cancer (PDTC: 12%; 262); Medullary Thyroid Cancer (MTC: 12%; 244), Anaplastic Thyroid Cancer (ATC: 10%; 220); Follicular Thyroid Cancer (FTC: 5%; 111); Hurthle Cell Thyroid Cancer (HCTC: 5%; 95); and others (1; 34). Median age at sequencing was 59 years. Gender distribution was higher in female (54%; n=1104) compared to male (46%; n=933). Ethnicities included 73.2% (n=1,493) White, 8.9% (n=178) Asian, and others.Most frequent genomic mutational alterations overall were BRAF (40.8%; 868) [96% (n=845) V600E, 0.6% (n=5) G469A, 0.6% (n=5) V600_K601delinsE, 0.2% (n=2) K601E, 0.2% (n=2) A404Cfs*9, and 2.7% (n=24) others]; TERT (35%; 624); NRAS (11.6%; 247); TP53 (11.6%; 247) and RET (9.3%; 197) genes. There was variability in genomic alterations between sub-histologies (Table 1). There was statistically significant co-occurrence between BRAF and TERT, TERT and TP53, TERT and NRAS alterations (p&amp;lt;0.001). Mutually exclusive alterations were BRAF and NRAS, BRAF and RET, TERT and RET, NRAS and RET, TP53 and RET, and BRAF and TP53 (p&amp;lt;0.001).Copy number alterations (CNA) were observed in 497 samples and were most frequent in CDKN2A, NKX2-1, CDKN2B, NF2, and CRKL genes (16.5%, 16%, 15.5%, 13.1%, and 13%). 362 oncogenic fusions were noted predominantly in CCDC6-RET, RET-NCOA4, ETV6-NTRK3, BRAF-Intragenic (20%, 7.2%, 3%, 1.6%). Conclusion: Genomic profiling identified full breadth of BRAF, RET and NRAS alterations and co-occurring oncogenic driver alterations. This approach may refine use of targeted therapy in thyroid cancer. Table 1. Histology Most frequent Alterations % n PTC BRAF 62.3% 724 TERT 32.7% 332 PDTC TERT 49% 117 NRAS 28.2% 74 MTC RET 71.3% 174 HRAS 7.8% 19 ATC TP53 58.2% 128 TERT 56.7% 106 FTC TERT 41% 27 NRAS 26.1% 29 HCTC TERT 41% 34 TP53 17.9% 17 Citation Format: Blessie Elizabeth Nelson, Mohammed Gouda, Jason Roszik, Mimi L. Hu, Maria Cabanillas, Vivek Subbiah. Genomic landscape of 2128 thyroid cancers from the aacr genie database: Implications for targeted therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4261.
Abstract 3105: Design principle of heparanase inhibitors: A combined <i>in vitro</i> and <i>in silico</i> study
Authors: Yuzhao Zhang, Meijun Xiong, Zixin Chen, Gustavo Seabra, Jun Liu, Chenglong Li, Lina Cui
Journal: Cancer Research (2023)

Abstract Heparanase (HPSE) is an endo-β-D-glucuronidase and the only known enzyme responsible for the cleavage of heparan sulfate (HS) side chains from heparan sulfate proteoglycans (HSPGs). The enzymatic activity of HPSE mediates ECM remodeling, regulates growth factors, and modulates related signaling pathways, thus HPSE has emerged as a novel therapeutic target for various diseases, including most types of cancers. In the last two decades, a number of HPSE inhibitors have been reported by several labs worldwide, with most of them belonging to the heparan sulfate mimics category. So far, few of the small molecule HPSE inhibitors have progressed into clinical trials and none has gained approval by regulatory agencies, leaving a blank in HPSE drug discovery. Here we present the discovery of a novel HPSE small molecule inhibitor by high-throughput screening using an ultrasensitive HPSE enzymatic detecting probe developed in our lab and provide the mechanisms of action behind the small molecule’s HPSE inhibitory activity. By doing a series of molecular dynamics (MD) simulations, we discovered the binding profiles on the derivatives of the lead compound. We summarized the essential structural features of the lead compound to provide insights into the design of future HPSE small molecule inhibitors. Citation Format: Yuzhao Zhang, Meijun Xiong, Zixin Chen, Gustavo Seabra, Jun Liu, Chenglong Li, Lina Cui. Design principle of heparanase inhibitors: A combined in vitro and in silico study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3105.
Abstract 42: <i>In vivo</i> subcutaneous and orthotopic cancer xenograft modeling in the SRG immunodeficient rat
Authors: Diane Begemann, Aida Javidan, Cynthia Dunn, Nicolas Johnston, R. Grace Walton, Valeriya Steffey, Ian Corbin, Niveen Fulcher, Cleusa De Oliveira, Hu Xu, Mila Uzelac, Andrew Deweyert, John A. Ronald, Susanne Schmid, Matthew O. Hebb, Fallon K. Noto
Journal: Cancer Research (2023)

Abstract Human cancer xenografts are a vital tool for understanding tumor biology, growth kinetics, and therapeutic efficacy using animal models. Historically, immunodeficient mice have been the standard rodent species for cancer xenograft modeling. However, an immunodeficient rat that supports a wide variety of human cancer cell types would provide a larger rodent strain for easier surgical manipulation, serial blood sampling, and provide a single model in which efficacy, pharmacokinetics, and toxicology can be performed. We have created a Sprague Dawley Rag2 -/-, Il2rg -/- rat (SRGTM OncoRat®) that provides a highly supportive environment for growing tumors of human origin. The SRG rat lacks B, T, and NK cells and readily supports the growth of multiple human cancer cell lines. The SRG rat is more immunodeficient than the Nude rat, suggesting it may be permissive to a wider variety of human cancer types. Here we demonstrate the utility of the SRG rat for both subcutaneous and orthotopic xenograft modeling. The SRG rat supports the growth of both lung and liver orthotopic cancers. In addition, the SRG rat supports the growth of orthoptic human glioblastoma multiforme in the brain. We use in vivo imaging to visualize tumor establishment and growth in subcutaneous, orthotopic, and metastatic models. Furthermore, our data show the ability of the SRG rat to support the growth of multiple different human cancer cell types subcutaneously in two different matrices, Matrigel® and VitroGel®. These data confirm that the SRG rat is an excellent host for studying human cancer. Our data demonstrate that the SRG rat has a high utility for studies using in vivo imaging, orthotopic tumor implantation, and standard subcutaneous tumor modeling. As the most immunodeficient rat commercially available, the SRG rat supports the growth of multiple human cancer types in a larger rodent strain relative to commercially available mouse models. Citation Format: Diane Begemann, Aida Javidan, Cynthia Dunn, Nicolas Johnston, R. Grace Walton, Valeriya Steffey, Ian Corbin, Niveen Fulcher, Cleusa De Oliveira, Hu Xu, Mila Uzelac, Andrew Deweyert, John A. Ronald, Susanne Schmid, Matthew O. Hebb, Fallon K. Noto. In vivo subcutaneous and orthotopic cancer xenograft modeling in the SRG immunodeficient rat [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 42.
Abstract 2742: Small interfering RNA targeting CD24 inhibits proliferation and migration of triple-negative breast cancer cells
Authors: Yanli Liu, Kun Cheng
Journal: Cancer Research (2023)

Abstract Triple-negative breast cancer (TNBC) is defined as the lack of human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), and estrogen receptor (ER) expression. TNBC accounts for 10-20% of all cancer cases and is more aggressive than other subtypes of breast cancer. Although chemotherapy is the mainstay of treatment for TNBC, its therapeutic efficacy is limited. Therefore, developing new therapies to address the unmet need of TNBC is urgently needed. CD24 protein is a heavily glycosylated glycosylphosphatidylinositol (GPI)-anchored surface protein. The high expression level of CD24 is observed in a variety of cancers, such as TNBC and ovarian cancer. CD24 plays an important role in tumor growth, invasion, and metastasis of different types of cancers. Besides, overexpression of CD24 in tumors is associated with resistance to chemotherapy agents and targeted therapies. Here, we design four siRNAs targeting different regions of the CD24 mRNA. The silencing activity of the predesigned siRNAs is evaluated by quantitative real-time RT-PCR and western blot. The biological effects of designed siRNAs on human breast cancer cells are investigated by cell proliferation, migration, invasion, cell cycle arrest, and apoptosis. The data demonstrate that the CD24 siRNAs significantly reduce CD24 expressions at both mRNA level and protein level in human TNBC cells. Moreover, silencing of CD24 suppresses breast cancer cell proliferation. Cell cycle assay shows that the anti-proliferation effect of CD24 siRNA is mediated by arresting the cells in the S phase. Furthermore, we reveal that silencing of CD24 inhibits migration and invasion of human breast cancer cells. Significant apoptosis is observed in CD24 siRNA transfected cells compared with the scrambled siRNA group. These data suggest that silencing CD24 using siRNA can be a potential therapeutic strategy for triple-negative breast cancer. Citation Format: Yanli Liu, Kun Cheng. Small interfering RNA targeting CD24 inhibits proliferation and migration of triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2742.
Abstract 2055: Prevalent focal amplification of oncogene in lung adenocarcinomas without canonical driver alterations
Authors: Seongyeol Park, Joonoh Lim, Kijong Yi, Boram Yi, Ryul Kim, Jaemo Koo, Kwon Joong Na, Samina Park, In Kyu Park, Chang Hyun Kang, Jeong Seok Lee, Young Seok Ju, Young Tae Kim
Journal: Cancer Research (2023)

Abstract Lung adenocarcinoma (LADC) is the most common type of lung cancer and a leading cause of death worldwide. Typical oncogenes that drive LADCs when mutated (referred to as canonical drivers) include EGFR (30-60%), KRAS (10-30%), and fusion oncogenes (~10%) involving ALK, RET, and ROS1. However, approximately 30% of lung adenocarcinomas lack canonical drivers, implying unseen kinds of genomic alterations. Here, we explore alterations beyond the scope of canonical drivers in LADCs (referred to as non-canonical drivers) using large-scale whole-genome sequencing (WGS) of LADCs. We gathered total 183 WGS of LADCs, 138 of which were from our previous study (Lee et al. Cell. 2019) and 45 were newly sequenced from surgically resected LADCs. For raw data processing, we used a standard WGS analysis pipeline from read mapping to variant calling. Variant filtering and downstream analyses were performed using in-house scripts. Genomic variants analyzed in this study include single-base substitution (SBS), indel, structural variation (SV), and copy number variation (CNV). As a result, we found that 53 cases (29%) had no canonical drivers (ND group). Intriguingly, LADCs without canonical drivers had a contrasting genomic landscape compared to LADCs with canonical drivers (CD group). First, the point-mutation burden was ~3-fold higher in the ND group than in the CD group (52,500 vs. 17,900 for SNVs, p&amp;lt;0.001). Mutational signature analysis revealed that these additional mutations are attributable mainly to tobacco smoking (by mutational signature SBS4) and APOBEC-mediated mutagenesis (SBS12 and SBS13) and that they are more enriched in the ND group (4,800 vs 2,600, p=0.03). Second, the ND group harbored more frequent focal amplifications. Recurrently amplified genes include TERT, IL7R, NKX2-1, CCND1, CCND3, CCNE1, and EGFR. The pattern of SVs suggest that the amplifications occurred through the formation of extra-chromosomal DNA involving multiple chromosomes or following chromothripsis. Overall, this study broadens our understanding of non-canonical drivers of LADCs. Similar analyses of thousands of cancers with clinical information of the patient will likely yield the functional impact of these driver mutations and may offer more opportunities for LADC treatment in the future. Citation Format: Seongyeol Park, Joonoh Lim, Kijong Yi, Boram Yi, Ryul Kim, Jaemo Koo, Kwon Joong Na, Samina Park, In Kyu Park, Chang Hyun Kang, Jeong Seok Lee, Young Seok Ju, Young Tae Kim. Prevalent focal amplification of oncogene in lung adenocarcinomas without canonical driver alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2055.
Abstract 3236: Optimizing mRNA vaccines and virus-mediated CAR T-cell therapy for immuno-oncology: Synthetic tools for gene modification
Authors: Ming Yang, Crystal Richardson, Prassanna Rao, Cassandra Koole, Michael J. Karney, Sumit Kumar
Journal: Cancer Research (2023)

Abstract With the success of mRNA vaccines during the COVID-19 pandemic and CAR T-cell therapies in clinical trials, there is growing opportunity for immunotherapies in the treatment of many types of cancers. Lentiviral vectors have proven effective at delivery of genetic material or gene editing technology for ex vivo processing, but the benefits and promise of Adeno-associated virus (AAV) and mRNA tools for in vivo immunotherapy have garnered recent interest. Here we describe complete synthetic solutions for immuno-oncology research programs using either mRNA-vaccines or virus-mediated cell and gene engineering. These solutions optimize workflows to minimize screening time while maximizing successful research results through: (1) Efficiency in lentiviral packaging with versatility in titer options for high-quality particles. (2) A high-throughput viral packaging process to enable rapid downstream screening. (3) Proprietary plasmid synthesis and preparation techniques to maintain ITR integrity through AAV packaging and improve gene delivery. (4) Rapid synthesis, in vitro transcription, and novel sequencing of mRNA constructs for complete characterization of critical components such as the polyA tail. The reported research demonstrates a streamlined approach that improves data quality through innovative synthesis and sequencing methodologies as compared to current standard practices. Citation Format: Ming Yang, Crystal Richardson, Prassanna Rao, Cassandra Koole, Michael J. Karney, Sumit Kumar. Optimizing mRNA vaccines and virus-mediated CAR T-cell therapy for immuno-oncology: Synthetic tools for gene modification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3236.
Abstract 2394: Activatable fluorogenic probe for two-photon imaging of heparanase <i>in vivo</i>
Authors: Zachary Rabinowitz, Zhishen Wang, Johnathan Somers, Jun Liu, Joyce Jiang, Nina Zhang, Lina Cui
Journal: Cancer Research (2023)

Abstract Heparanase, an endo-β-glucuronidase, is the only known enzyme that is responsible for the cleavage of heparan sulfate chains of heparan sulfate proteoglycans. Its enzymatic activity plays a key role in remodeling and degradation of the extracellular matrix, generation of biologically active carbohydrate fragments, and liberation of effector molecules, such as growth factors and chemokines, that are bound to the heparan sulfate side chains. Overexpression of heparanase has been implicated in most types of cancers and various inflammatory diseases that usually involve extensive heparan sulfate degradation and extracellular matrix remodeling. In particular, the role of heparanase in cancer is highly significant as it regulates multiple biological activities that fosters tumor progression, angiogenesis, metastases. Consequently, heparanase has been considered a biological target for various therapeutic applications including anti-cancer drug development. However, one of the major challenges in this research area is the development of robust and feasible heparanase probes to study the enzymes’ fundamental biology in the extracellular matrix, to provide heparanase-targeted diagnostics, and to aid in drug discovery efforts. Our lab has been developing various small-molecule-based heparanase activatable probes, and we have successfully developed chemical strategies that allow sensitive detection of heparanase activity in various contexts. Two-photon microscopy allows for deeper tissue penetration, excellent spatial resolution, and efficient light detection with reduced photobleaching effects. Herein, we extend our chemical strategies to develop a heparanase-activatable two-photon fluorogenic probe for real-time detection of heparanase activity in animal models of highly-aggressive brain cancer using two-photon imaging. Citation Format: Zachary Rabinowitz, Zhishen Wang, Johnathan Somers, Jun Liu, Joyce Jiang, Nina Zhang, Lina Cui. Activatable fluorogenic probe for two-photon imaging of heparanase in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2394.
Abstract 3219: Development of a quality-of-life assessment module in patients with radiation dermatitis
Authors: Olivia S. Allen, Alyson B. Moadel-Robblee, Jana Fox, Johnny Yap, Beth N. McLellan
Journal: Cancer Research (2023)

Abstract Introduction: Radiation dermatitis (RD) is one of the most common side effects of radiation therapy (RT), experienced by up to 95% of oncology patients. RD can be progressive, painful, and difficult to manage, thereby profoundly affecting patients’ quality of life (QOL). Current QOL assessments address dermatologic or oncologic concerns, with no existing tool integrating both areas to enable assessment of RD-specific QOL. Furthermore, RD grade does not consistently correlate with QOL scores in these assessments. The aims of this study are to identify unexplored QOL concerns in patients with RD and to create a new, RD-specific, validated assessment module to evaluate QOL in this patient population. Methods: We conducted open-ended interviews with 20 patients with breast cancer with current or former RD during a radiation oncology clinic visit to determine RD-specific QOL concerns. We analyzed the most high-yield concerns to determine areas that are not addressed by current QOL assessments. With a workgroup of radiation oncologists, dermatologists, a psycho-oncologist, and patients, we evaluated our findings and used common themes to generate a new QOL survey. Results: Among our patient cohort, 3 (15%) were undergoing current RT, 7 (35%) were at their first post-RT visit, 9 (45%) were at a follow-up visit within 12 months of completing RT, and 1 (5%) was at a follow-up visit over 12 months after completing RT. We uncovered four key areas affecting patients that are not incorporated into current QOL assessments: changes in clothing in 18 (90%) patients (e.g. wearing looser clothing, changing to a different bra, using a layer of bandages), changes in skin color in 17 (85%) patients (hyper- or hypopigmentation), changes in sleep due to skin changes in 13 (65%) patients (e.g. difficulty finding a comfortable position), and changes in ability to use the affected side in 9 (45%) patients (e.g. carrying items, avoiding contact with irritating material). We incorporated these four areas of concern into a six-question, RD-specific QOL assessment module to the Skindex-16, a validated and widely used QOL assessment in dermatology. Conclusions: This pilot study enabled us to discover previously unexplored QOL concerns in patients with RD that are not addressed in current dermatology and oncology focused assessments. Future work includes validation of this module in patients with acute RD with the goal of identifying opportunities to optimize treatment and enhance patient-centered care for this population. Citation Format: Olivia S. Allen, Alyson B. Moadel-Robblee, Jana Fox, Johnny Yap, Beth N. McLellan. Development of a quality-of-life assessment module in patients with radiation dermatitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3219.